DNA polymerase beta plays an essential role in the base excision repair pathway necessary to cleanse the genome of simple base lesions and abasic sites. Abasic sites arise in DNA from spontaneous base loss (depurination) and DNA-damage specific glycosylases that hydrolyze the N-glycosidic bond between the deoxyribose and the damaged base. DNA polymerase beta contributes two enzymatic activities: DNA synthesis and deoxyribose-phosphate removal through nucleotidyl transferase and lyase mechanisms, respectively. The active site for each of these activities resides on a distinct domain of the protein: 31-kDa polymerase domain and amino-terminal 8-kDa lyase domain. The simple organization of each domain and the ability to assay each activity have hastened our understanding of the faithful replication of DNA during repair synthesis and the flux of intermediates through single nucleotide base excision repair and its alternate pathways.